High Dosage Omega-3 Fatty Acids Outperform Existing Pharmacological Options for Migraine Prophylaxis: A Network Meta-Analysis

Migraine is a highly prevalent neurologic disorder with prevalence rates ranging from 9% to 18% worldwide. Current pharmacologic prophylactic strategies for migraine have limited efficacy and acceptability, with relatively low response rates of 40% to 50% and limited safety profiles. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are considered promising therapeutic agents for migraine prophylaxis. The aim of this network meta-analysis (NMA) was to compare the efficacy and acceptability of various dosages of EPA/DHA and other current Food and Drug Administration–approved or guideline-recommended prophylactic pharmacologic interventions for migraine. Randomized controlled trials (RCTs) were eligible for inclusion if they enrolled participants with a diagnosis of either episodic or chronic migraine. All NMA procedures were conducted under the frequentist model. The primary outcomes assessed were 1) changes in migraine frequency and 2) acceptability (i.e., dropout for any reason). Secondary outcomes included response rates, changes in migraine severity, changes in the frequency of using rescue medications, and frequency of any adverse events. Forty RCTs were included (N = 6616; mean age = 35.0 y; 78.9% women). Our analysis showed that supplementation with high dosage EPA/DHA yields the highest decrease in migraine frequency [standardized mean difference (SMD): −1.36; 95% confidence interval (CI): −2.32, −0.39 compared with placebo] and the largest decrease in migraine severity (SMD: −2.23; 95% CI: −3.17, −1.30 compared with placebo) in all studied interventions. Furthermore, supplementation with high dosage EPA/DHA showed the most favorable acceptability rates (odds ratio: 1.00; 95% CI: 0.06, 17.41 compared with placebo) of all examined prophylactic treatments. This study provides compelling evidence that high dosage EPA/DHA supplementation can be considered a first-choice treatment of migraine prophylaxis because this treatment displayed the highest efficacy and highest acceptability of all studied treatments. This study was registered in PROSPERO as CRD42022319577.


Introduction
Migraine is a highly prevalent neurologic disorder with a prevalence rate of 9.1% to 18.2% [1,2].Migraine warrants more attention because it causes significant clinical morbidity, diminishes quality of life, and is associated with potential headache medication overuse around the world.Multiple treatment strategies for migraine prophylaxis, which is defined as migraine frequency reduction [3][4][5], are currently under investigation [6][7][8].However, the response rates for many migraine prophylaxis therapies appear modest (i.e., ~40%-50%) [9].Because of the limited efficacy, obvious adverse events, and insufficient evidence for the current pharmacologic treatments to manage prevention, there is an unmet need for more effective and highly acceptable agents to prevent migraine.Although a recent large-scale network meta-analysis (NMA) addressed several new approaches to prevent migraine, such as noninvasive neuromodulation strategies [10], use of monoclonal anticalcitonin gene-related peptide (CGRP) antibodies [11], and supplementation with exogenous melatonin [12], the efficacy and acceptability of the aforementioned treatments still were limited.We aimed to gather and evaluate the evidence for EPA and DHA as a potent preventive migraine therapy that is easily tolerated by patients to improve long-term compliance.
Although the hypothesized benefits of EPA/DHA in migraine prophylaxis are highly promising [20], the supporting evidence from randomized controlled trials (RCTs) remains unclear [21,22].This discrepancy might be due to the following issues.First, different doses of EPA/DHA appear to vary in effectiveness in migraine prophylaxis.Second, some RCTs did not use a "placebo-controlled" design.In clinical trials for headache and pain treatment, a placebo effect was found to be as high as 40% to 55% [23][24][25].Third, the age-dependent treatment efficacy (i.e., adult compared with child) is another potential confounding issue [21,26].Although a prior meta-analysis attempted to resolve this controversy, its overall results were inconclusive [27].
As indicated above, the significant challenge of evaluating potential differences in prophylactic effectiveness of various doses of EPA/DHA cannot be simply resolved by the traditional pairwise meta-analysis or single RCT.Rather, NMA is necessary to improve the power of multiple comparisons of treatment efficacy and possible superiority of individual pharmacologic interventions of different dosages, thereby providing potentially significant detailed evidence-based information to guide future clinical practice.The primary aim of this study was to compare the efficacy and safety profile of different dosages of EPA/DHA with Food and Drug Administration (FDA)-approval or guideline-recommended pharmacologic interventions, based on changes in migraine frequency in patients with migraine.

Statement of Significance
Based on 40 randomized controlled trials and 6616 participants, high dosage prophylactic EPA/DHA supplementation can be considered a first-choice treatment of migraine prophylaxis because this treatment displayed the highest efficacy and highest acceptability of all studied treatments.

General guidelines applied in the current study
The present NMA followed the PRISMA 2020 guidelines (Supplemental Table 1) and AMSTAR2 (Assessing the Methodological Quality of Systematic Review) guidelines.The current study was approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (TSGHIRB No. B-109-29) and was registered in PROSPERO (CRD42022319577).

Search strategy and selection criteria
In the NMA, our search strategy consisted of 2 stages.In the first stage, we conducted a systematic review of publications retrieved from PubMed, Embase, ProQuest, ScienceDirect, Cochrane CENTRAL, ClinicalKey, Web of Science, and clinicaltrials.govfrom inception to 20 March, 2022, to search for RCTs using ω-3 or ω-6 PUFAs in the management of migraine with/without aura.In the second stage, to include studies about the efficacy/safety of the FDA-approved or guidelinerecommended [6] oral forms of medications used for management of migraine with/without aura, we performed an additional search to find RCTs using topiramate, valproate, propranolol, timolol, amitriptyline, venlafaxine, lisinopril, frovatriptan, or candesartan in migraine prevention.We focused on oral medications because of the potential difference between the placebo effect of an oral placebo and that of injected placebo (i.e., the injected form exhibited the highest pain-free rate in migraine management compared with other forms of placebo) [28].From perspective of statistics, the NMA was based on the hypothesis of similarity.To be specific, according to the similarity hypothesis, the placebo effect of the injected form should be similar to that of the oral form of placebo; otherwise, the similarity hypothesis would not be established, and the NMA would be invalid.Therefore, we did not include the injected forms of treatment in the present NMA in order to fulfill the basic similarity hypothesis of NMA.Specifically, we did not include the botulinum toxin (Bot) or CGRP treatments in this NMA.No language restrictions were applied.The detailed search strategy and keywords applied to each database are depicted in Supplemental Table 2.We also conducted manual searches for potentially eligible articles from the reference lists of review articles or pairwise meta-analyses.

Inclusion and exclusion criteria
The PICO applied in the present NMA was as follows: 1) Participants: patients with migraine, either episodic, chronic, or nonspecified; 2) Intervention: EPA/DHA supplementations or FDA-approval/guideline-recommendation medication to manage migraine; 3) Comparison: placebo control; and 4) Outcome: changes in migraine frequency or response rate.We chose the target of migraine frequency reduction based on the definition of migraine prevention in the previous guidelines [2,4,5], which define the migraine prevention to be "migraine frequency reduction."The response was defined as "!50% improvement from baseline."To improve the quality of the included articles and to reduce the unwanted impact of a potential placebo effect (in clinical trials for headache and pain treatment, a placebo effect is found to be as high as 40%-55%) [23][24][25], we only included peer-reviewed published articles reporting RCTs with either placebo-controlled or active-controlled with applied placebo in the study design.The targets for comparison were pharmacologic interventions used for prophylaxis in patients with migraine but not for acute treatment to migraine attack.Therefore, the inclusion criteria were as follows: 1) RCTs of migraine patients; 2) trials investigating pharmacologic interventions for migraine prevention; 3) human studies; and 4) placebo-controlled studies.
The exclusion criteria were as follows: 1) studies that were not clinical trials in humans; 2) studies that were not RCTs; 3) studies that recruited patients without migraine; and 4) studies that did not use a placebo.In cases of duplicated data (i.e., different articles based on the same sample), we only included the reports with more information and larger sample sizes.

Data extraction
Two authors independently screened the studies, extracted relevant data from the articles, and assessed risk of bias among the included studies.Cases of discrepancy were adjudicated by the corresponding author (YLS, CMH, KPS, and PYL).We divided EPA/DHA supplementations into 3 dosage groups: 1) EPAþDHA <900 mg/d, 2) 900-1500 mg/d, and 3) 1500 mg/d or higher.If the data was not available in the manuscript, we contacted the corresponding author or coauthors to obtain the original data.

Outcome definition
The primary outcomes were 1) changes in migraine frequency associated with the pharmacologic interventions and 2) acceptability (i.e., dropout rate), where dropout was defined as patient withdrawal from the study before its end for any reason.The secondary outcomes were 1) response rate, which was defined as a 50% reduction in baseline frequency of migraine days after pharmacologic interventions; 2) changes in migraine severity; 3) changes in frequency of rescue medication use; and 4) rate of any adverse events.The selected primary outcomes (frequency of migraine attack and acceptability) and secondary outcomes (response rate and frequency of any adverse events) are widely used in various NMAs of migraine management [10,12].

Cochrane risk-of-bias tool
Two independent authors evaluated risk of bias (interrater reliability, 0.86) for each domain described in the Cochrane risk-of-bias tool.

Statistical analysis
The NMA was performed using STATA (version 16.0; Stata-Corp LLC).For continuous data, we calculated summary standardized mean differences (SMDs) with 95% confidence intervals (CIs).For categorical data, we estimated summary odds ratios (ORs) with 95% CIs.For categorical data, we used a 0.5 zero-cell correction during the meta-analysis procedure.However, if in one study both intervention and control arms were 0, we did not apply this correction procedure because of risk of increasing bias [29].We used the most frequent NMA model to compare the effect sizes among studies with the same interventions.All comparisons were 2-tailed, and a P value 0.05 denoted statistical significance.Heterogeneity among the included studies was evaluated using the tau value, which is the estimated standard deviation of the effect across the included studies.Regarding the meta-analysis procedure applied in the current study, we used mixed comparisons with generalized linear mixed models to analyze the direct and indirect comparisons for NMA.For comparisons among multiple treatment arms, we combined direct and indirect evidence from the included studies.In the present NMA, we used a suite of STATA programs using "mvmeta" for data manipulation [30].We used the restricted maximum likelihood method to evaluate between-study variance.To increase the clinical application, we calculated relative ranking probabilities between the preventive effects of all treatments studied for the target outcomes.In brief, the surface under the cumulative ranking curve (SUCRA) is the percentage of the mean rank of each pharmacologic intervention relative to an imaginary intervention that is the best without uncertainty [31].Finally, we evaluated potential inconsistencies between the direct and indirect evidence within the network using the loop-specific approach and local inconsistencies using the node-splitting method.Further, we used the design-by-treatment model to evaluate global inconsistencies throughout the entire NMA.We used comparison-adjusted funnel plots and Egger regression to evaluate potentially small study effects and publication bias.Finally, we performed subgroup analyses dividing RCTs in subgroups of 1) adults compared with children; 2) episodic migraine compared with chronic migraine; or 3) excluding trials with high risk-of-bias items.

Eligibility of the retrieved studies and treatment arms
Figure 1 depicts the flowchart of the present NMA.After the initial screening procedure, a total of 78 articles were considered for full-text review, of which 38 were excluded for various reasons (Supplemental Table 3).Finally, 40 RCTs were included in the current study (Table 1) [18,21,22,25,26,.The overall network structure of the treatment arms is provided in Figure 2A, B.

Characteristics of the included studies
A total of 6616 participants (mean age 35.0 y, range 10.36-46.2y; mean female proportion 78.9%, range 20.0-97.5)were included.The mean treatment duration was 18.0 wk (from 4.0 to 26.0 wk).The mean overall study duration (i.e., treatment þ posttreatment follow-up) was 19.0 wk (from 4.0 to 30.0 wk).

Subgroup of episodic compared with chronic migraine.
When focusing on RCTs of participants with episodic migraine, only valproate (SMD: À0.76; 95% CI: À1.18, À0.33) was associated with significantly better improvements in the frequency of episodic migraine days than placebo (Supplemental Table 4C, Supplemental Figure 1C, and Supplemental Figure 2C).According to the SUCRA, valproate was associated with the greatest improvement in the frequency of episodic migraine days of all the pharmacologic interventions (Supplemental Table 5D).
When focusing on RCTs with chronic migraine participants, none of the investigated treatments were associated with significantly different changes in the frequency of chronic migraine days compared with the placebo (Supplemental Table 4D, Supplemental Figure 1D, Supplemental Figure 2D, and Supplemental Table 5E).

Primary outcome: 2) acceptability of dropout rates
We also evaluated the acceptability of the investigated pharmacologic interventions using the NMA.In brief, only valproate (OR: 1.66; 95% CI: 1.08, 2.55) was associated with significantly higher dropout rates than the placebo (Table 3 and Figure 3B).According to the SUCRA, AmLowPUFA (OR: 0.43; 95% CI: 0.09, 2.02 compared with placebo) was associated with the lowest dropout rate (Supplemental Table 5F).

Secondary outcome: response rate
The NMA results showed that AmLowPUFA (OR: 51 1F, and Supplemental Figure 2F).According to the SUCRA, AmLowPUFA was associated with the highest response rate of all the pharmacologic interventions, followed by ToN and candesartan (Supplemental Table 5G).

Risk of bias and publication bias
We found that 63.6% (178/280 items), 27.5% (77/280 items), and 8.9% (25/280 items) of the included studies had an overall low, unclear, and high risk of bias, respectively.The funding sources and concealing procedure after randomization mainly contributed to the high and unclear risk of bias, respectively (Supplemental Figure 3A, B).
Funnel plots of publication bias and Egger test across the included studies (Supplemental Figure 4A-J) revealed general symmetry and no significance among the recruited studies in this NMA.The inconsistency test revealed nonsignificant inconsistency in the present NMA (Supplemental Tables 6-8).The results of GRADE evaluation are listed in Supplemental Table 9.In brief, the overall quality of evidence ranged from low to medium.

Discussion
To the best of our knowledge, the present NMA is the first to investigate associations between the effects of migraine prophylaxis with EPA/DHA supplements compared with other FDA-approved/guideline-recommended medications.The results of this study demonstrated that EPA/DHA supplements conferred noninferior prophylactic effects compared with other FDA-approved/guideline-recommended medications in migraine patients in both efficacy and acceptability.To be specific, migraine prophylaxis with HighPUFA was associated with the greatest improvements in migraine frequency and migraine severity of all the investigated treatments.However, EPA/DHA supplements had similar acceptability compared with other pharmacologic treatments and placebo.The combination of FDA-approval/guideline-recommended medications and EPA/DHA supplements (i.e., amitriptyline plus EPA/DHA) was also associated with the highest response rate of all of the studied treatments.Finally, treatment with EPA/DHA supplementation was associated with a favorable low frequency of adverse events compared with placebo and other pharmacologic interventions.
The most important result of the present NMA is that EPA/DHA supplementation was associated with a superior prophylactic effect on migraine frequency/severity compared with other FDA-approved/guideline-recommended medications.As mentioned previously, the most widely accepted etiologies of migraine are 1) the neuroinflammation theory; 2) TVGT pathway; and 3) the vasodilation theory.The effects of Pairwise (upper-right portion) and network (lower-left portion) meta-analysis results are presented as estimate effect sizes for the outcome of improvement in frequency of migraine attack.Interventions are reported in order of mean ranking of treatment effect, and outcomes are expressed as SMD (95% confidence interval).For the pairwise meta-analyses, SMD <0 indicates the treatment specified in the row showed better improvement in migraine attack frequency than that specified in the column.For the network meta-analysis, SMD < 0 indicates the treatment specified in the column showed better improvement in migraine attack frequency than that specified in the row.Abbreviation: Ami, amitriptyline; AmLowPUFA, low-dose n- prescription of EPA/DHA supplements contradicts these etiologies.Specifically, EPA/DHA reduced the expression of tumor necrosis factor α (TNF-α) [67], cyclooxygenase-2/NO synthase induction [68], and IL-1β concentrations [69], which are believed to contribute to neuroinflammation and neurogenic pain in the central nervous system.Furthermore, the addition of EPA/DHA was found to have a beneficial effect on reducing nociceptive responses in patients with neuropathic pain, which might occur through activation of the opioid system [19,70,71].
In addition, EPA/DHA supplements helped restore serotonin and dopamine concentrations, which play an important role in the TVGT nociceptive pathway [72].Finally, dietary EPA/DHA can also inhibit TNF-α expression [67], which may lead to reduced cerebral vasodilation.In summary, the above evidence supports the hypothesis that EPA/DHA supplementation ameliorates dysregulation of many pathways underlying migraine-related pathophysiology and confers potent migraine prophylaxis.In addition to high efficacy, patient acceptance and compliance with EPA/DHA supplementation is revealed by this NMA and a prior large-scale metaanalysis [73].All these studies also show the clinically significant finding of higher rates of adverse events with traditional pharmacologic regimens for migraine prophylaxis such as valproate, which limits clinical options for managing migraine [74].Therefore, the evidence from this NMA provides a sound rationale for future large-scale RCTs to investigate the potential role and optimal dosing of EPA/DHA supplementation in migraine prophylaxis.However, the interpretation of our NMA findings require caution before gathering any supporting or opposing data from head-to-head RCTs.To the contrary, although we recognize that there are currently several RCTs of dietary ω-3 fatty acid supplements addressing migraine prevention [20,75], we did not include them in our NMA because they did not include adequate placebo control in their study design [20] or recruited patients with chronic headache but not migraine [75].As addressed in methods section, a potential biased placebo effect (in clinical trials for headache and pain treatment, a placebo effect is found to be high as high as 40%-55%) [23][24][25] might impose bias in the present NMA, so we excluded "studies that did not use placebo" in our study design.Also, the design of control groups in dietary ω-3 fatty acid RCTs often uses concurrent prophylactic pharmacy, which would result in a difference between the control groups in other RCTs that might violate the similarity hypothesis of NMA.In addition, the inclusion of patients with a different diagnosis might also violate the basic similarity hypothesis of NMA.

Strengths and limitations
This pilot NMA has several strengths.First, due to the large numbers of included RCTs and participants (40 RCTs and 6616 participants), the present NMA could provide more information and higher evidence than RCTs and traditional meta-analyses.Second, we only included RCTs and trials using placebo to increase the reliability of the present study.As addressed before, in pain and headache research, the placebo effect has been reported to account for 40% to 55% of the treatment effect [25].Third, to be more clinically applicable, we performed additional searches to include RCTs of FDA-approved/guideline-recommended regimens in the present study, which could help clinicians to make relevant comparisons with traditional pharmacologic interventions.
There are also several limitations to the present NMA.First, some analyses in this study were limited by underpowered statistics, including heterogeneity in the characteristics of the participants (e.g., underlying diseases, different concomitant medications, wide variety of ages, lack of uniform diagnostic FIGURE 3. Forest plot of the primary outcomes with reference to placebo: (A) changes in migraine frequency and (B) acceptability in dropout rate.Specific treatments were associated with (A) better improvement in migraine frequency than the placebo if the standardized mean difference was <0 or (B) better acceptability in dropout rate than the placebo if the odds ratio was < 1. Ami, amitriptyline; AmLowPUFA, low dosage n-3 PUFA þ amitriptyline; Can, candesartan; Cyc, cyclandelate; HighPUFA, high dosage n-3 PUFA; Lam, lamotrigine; Lis, lisinopril; Max, Maxepa (ω-3 polyunsaturated fatty acids, eicosapentaenoic acid/docosahexaenoic acid: 180 mg/120 mg Â 6 pills); MedPUFA, medium dosage n-3 PUFA; Nor, nortriptyline; Pla, Placebo; Pro, propranolol; PUFA, polyunsaturated fatty acid; ToN, topiramate þ nortriptyline; Top, topiramate; TPr, topiramate þ propranolol; Val, valproate; VaLowPUFA, low dosage n-3 PUFA þ valproate; Ven, venlafaxine.cri-teria for migraine, and trial duration) and the small number of trials in some treatment arms.Second, although there was more and more evidence addressing the efficacy of different ratios of EPA/DHA, we could not further classify studies due to the limited information regarding EPA/DHA ratio.Third, in order to fulfill the basic similarity hypothesis of NMA, we did not include the injected forms of treatment, such as Bot and CGRP treatment, in the present NMA.Although statistically, this is a necessary strategy, this exclusion might limit the clinical application of this NMA.Fourth, some of the included RCTs have potential quality concerns in their methodology.Therefore, readers should use caution when interpreting the results of the present NMA.Finally, although our study is strengthened by multiple comparisons of different treatments via NMA, generalization of our results is still limited by the potential bias resulting from the funding sources within the included RCTs.Similarly, the main findings regarding the efficacy of EPA/DHA in migraine prophylaxis primarily came from the few RCTs using EPA/DHA products [18,21,22,26,32].Therefore, clinicians should avoid overinterpretation of the findings in the present NMA and apply them in a relatively conservative way.

Conclusions
This NMA suggests that prophylactic EPA/DHA supplementations are associated with better reduction of the frequency and severity of migraine episodes and fair acceptability.In addition, these beneficial effects were not inferior to those of current pharmacologic regimens approved by the FDA or treatment guidelines.Our findings provide a rationale for designing future large-scale RCTs to investigate optimal dosing of EPA/DHA supplementation in migraine patients.However, because of the numbers of RCTs using EPA/DHA products, clinicians should avoid overinterpretation of the findings of the present NMA and apply them in a relatively conservative way.001) jointly funded by Health Education England and the National Institute for Health Research (NIHR).Brendon Stubbs is part funded by the NIHR Biomedical Research Centre at South Pairwise (upper-right portion) and network (lower-left portion) meta-analysis results are presented as estimate effect sizes for the outcome of dropout rate.Interventions are reported in order of mean ranking of tolerability, and outcomes are expressed as OR (95% confidence interval).For the pairwise meta-analyses, OR < 1 indicates the treatment specified in the row had a lower dropout rate than that specified in the column.For the network meta-analysis, OR < 1 indicates the treatment specified in the column had a lower dropout rate than that specified in the row.

TABLE 1
Characteristics of the included studies

TABLE 2
League table of changes in frequency of migraine attacks

TABLE 3
League table of dropout rates